Human cytomegalovirus (HCMV) is the most common infectious cause of permanent births defects worldwide, often resulting in auditory and cognitive abnormalities and in rare cases even in multi-organ failure and death (1-4). Congenital HCMV infection occurs in 0.05 to 1% of all pregnancies, and 10 to 25% of congenitally infected newborns develop long-term developmental disabilities (2-6). Annual incidence of HCMV seropositive (HCMV+) infants at birth range from 35,000 in Brazil to 40,000 in the United States, and 250,000 in India (5). In fact, persistent newborn medical conditions are more frequently associated with congenital HCMV infection than with other well-known childhood diseases such as trisomy 21, spina bifida, or fetal-alcohol syndrome (2, 4, 7-10). Besides its leading role in permanent birth defects, HCMV is also a major cause of morbidity and mortality in hematopoetic stem cell and solid organ transplant recipients (11-13). Based on the societal and financial health burden and in the absence of effective treatment options, HCMV has been assigned as one of the highest priority vaccine targets (14, 15). However, incompletely defined correlates of protection, lack of animal models susceptible to HCMV infection, insufficiently powered vaccine trials, and general unawareness, are a number of obstacles that have hampered the development of an effective and safe HCMV vaccine (16).
High titer and durable neutralizing antibodies (NAbs) that block glycoprotein complex-mediated entry into host cells are thought to be essential to prevent or control congenital HCMV infection. For many decades, HCMV subunit vaccine research has primarily focused on stimulation of NAbs targeting the major essential envelope glycoprotein B (gB), culminating in the encouraging findings obtained with recombinant gB admixed in adjuvant MF59 (17). In phase II clinical trials, gB/MF59 has been shown to reduce viremia and the need for antiviral therapy in solid organ transplant recipients and provide moderate efficacy of 38-50% to prevent primary infection in young women of childbearing age (17-20). These findings have spurred interest to improve vaccine-mediated induction of NAb responses as an approach to improve protective efficacy beyond that observed with gB/MF59.
In recent years it has been recognized that HCMV entry into fibroblasts (FB) and epithelial/endothelial cells (EpC/EnC) occurs by alternate routes of entry that are blocked by NAbs of varying potency and cell-type specificity (21-23). HCMV infection of FB depends on the major essential envelope glycoprotein complexes (gC) gM/gN, gB, and gH/gL (22, 23). In contrast to FB entry, HCMV infection of EpC/EnC requires an additional complex formed by gH/gL, UL128, UL130, and UL131A (PC) (21, 24-26). A third gH/gL complex composed of gH/gL/gO appears necessary for entry into both FB and EpC/EnC, though this remains controversial (27-31). NAbs targeting the major gC block both HCMV entry routes (32); however, NAbs recognizing predominantly conformational epitopes formed by two or more of the UL128/130/131A subunits of the PC are unable to prevent FB entry, though they have potency to interfere with EpC/EnC infection that dramatically exceed that of NAb targeting the major gC (32, 33).
Many vaccine strategies based on either live-attenuated viruses, viral vector systems or purified proteins confirm that the PC is the major target of NAbs blocking HCMV infection of EpC/EnC (33-36). All of these vaccine approaches consistently demonstrate in animal models that the PC has superior immunogenicity to elicit NAbs against EpC/EnC entry compared to PC subunit subsets (gH/gL or UL128/UL130/UL131A) or gB (33-36). These studies also show that vaccine approaches employing the PC are equally or even more effective than gB-based vaccine strategies to induce NAbs blocking FB entry (33, 34, 36). Consequently, PC subunit vaccines elicit high titer EpC/EnC specific NAb responses and less potent NAbs against FB entry, which is consistent with the NAb response induced by HCMV during natural infection (37-39).
Although the mechanisms through which HCMV crosses the placenta are still debated, cytotrophoblasts (CTB) including their syncytial forms and progenitors are thought to be the key mediators involved in all potential HCMV vertical transmission routes (40-44). These cells build a bridge at the fetal-maternal interface and can be efficiently infected by HCMV in vitro and in vivo (10, 43-46). In addition, infection of CTB in early gestation often results in placental developmental abnormalities (44, 46-48). However, NAbs that interfere with HCMV infection of placental cells are only poorly characterized. A recent study has shown that HCMV infection of CTB progenitor cells can be efficiently blocked by NAbs to gB, although NAbs targeting the PC are unable to interfere with CTB progenitor infection (49, 50). Whether PC-specific NAbs are able to prevent infection of differentiating CTB is unknown.
Accordingly, there remains a need to develop highly effective antibodies to neutralize CMV infections, particularly HCMV infections.